Rheumatoid arthritis is an autoimmune disease that can cause chronic inflammation in joints and other parts of the body and leads to permanent joint damage and deformities. If not treated, rheumatoid arthritis can lead to substantial disability and pain due to the damage of joint function, which ultimately leads to shorter life expectancy. At present, the treatment of rheumatoid arthritis is far from satisfactory, and there is still a need to find new drugs that can be used for its treatment. Rheumatoid arthritis is a chronic disease that requires long-term therapy and repeated ingestion of the drugs. While long-term treatment may be a heavy burden on patients as well as doctors as the patient may be intolerant of the drug or become intolerant of the drug. In addition, higher dosage or frequency may lead to side effects of discomfort and/or lower patient compliance. The high incidence of rheumatoid arthritis (about 0.8% of adult worldwide) indicates its great social impact. The goal of rheumatoid arthritis therapy is not just to slow the progress of the disease, but also to relieve the pain in order to prevent joint damage and improve the quality of human life.
Crohn's disease is a type of inflammatory bowel disease that causes inflammation of the digestive tract, abdominal pain, severe diarrhea, intestinal obstruction, ulcers, fistula, anus cracks and other conditions, and is recurrent. In addition, people with Crohn's disease are at risk of malnutrition because their intestine cannot absorb the nutrients their bodies need from their diets. Inflammation caused by Crohn's disease may involve different areas of the human digestive tract, usually deep into the layers of intestine tissue, causing both pain and weakness, and even life-threatening complications. The recurrence rate of this disease is related to the extent of lesions, the enhancement of disease invasion, the prolongation of the disease course, the increase of age and other factors, and the mortality rate is also increased. Therefore, there is a need to develop therapeutic drugs that have a beneficial effect on this disease.
“JAK” refers to the Janus kinase (JAKs) family, a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors, and is widely involved in many important biological processes such as inflammation, autoimmunity and immune regulation. The Janus kinase family comprises the following four JAK family members: JAK1, JAK2, JAK3 and TYK2. Among them, inhibition of JAK1 is essential for the anti-inflammatory treatment, while inhibition of JAK2, JAK3 and TYK2 is not necessary for anti-inflammatory treatment, and their inhibition process may cause some adverse reactions. For example, inhibition of JAK2 may causes anemia and inhibition of JAK3 may inhibit immune function. JAK1 is a target for immune-inflammatory diseases, and its inhibitors are beneficial for the treatment of immune inflammatory disorder diseases such as rheumatoid arthritis and Crohn's disease.
Filgotinib (GLPG0634) is a JAK1 selective inhibitor with IC50 of 10 nM, 28 nM, 810 nM, and 116 nM for JAK1, JAK2, JAK3, and TYK2, respectively. Among them, IC50 (half maximal inhibitory concentration) refers to the measured semi-inhibitory concentration, which can indicate the half amount of a drug or substance (inhibitor) in inhibiting certain biological procedures. The lower the value, the stronger the inhibition ability of the drug is. Therefore, Filgotinib shows a high degree of selectivity in inhibiting JAK1. Clinical trials by Gilead have shown that Filgotinib does not cause an anemia and abnormal increase in low density lipoprotein (LDL), and the free form is registered for clinical use. The results show that Filgotinib has a very good application prospect in the treatment of rheumatoid arthritis and Crohn's disease.
The chemical name of Filgotinib is: N-[5-[4-[(1,1-dioxo-1-thiomorpholin-4-yl)methyl]phenyl][1,2,4]triazolo [1,5-a]pyridin-2-yl]cyclopropanecarboxamide. The chemical formula is C21H23N5O3S. The molecular weight is 425.5. The chemical structure is shown as below:

WO2010149769A1 (which is incorporated herein by reference) disclosed the confirmation, preparation and use of the free form of Filgotinib, however, the patent does not disclose information of the final solid form of Filgotinib free form. CN105111206A proved that the solid in WO2010149769A1 is amorphous. The analysis of prior art of the free form are as follows:
PatentCrystalline formDisadvantagesCN105960407APattern 1, 3 and 4Preparation methods of the three crystalline forms are allof free formcomplicated. Heating cooling cycle between ambienttemperature and 50° C. is required. XRPD pattern indicatesthat the crystallinity of pattern 3 is poor.CN105061420AForm H1, H2, H3,The preparation methods are complicated, and all of theH4 of free formpreparation methods need the procedure of heating to ahigh temperature of 70-90° C. and then cooling to 0-30° C.CN105198880AForm A of freeThe yield is low, ranging from 76% to 88%. XRPD patternformindicates that the crystallinity is poor.CN105218539AForm B of freeStability is poor. Sample was tested by XRPD after beingformplaced at 92.5% humidity for 5 days and 10 days and theresults show that the stability is poor. The solubility is low.The solubility in water is 41.28 μg/mL. The yield is low,and is in the range of 70-86%.CN105198879AForm C of freeStability is poor. Sample was tested by XRPD after beingformplaced at 92.5% humidity for 5 days and 10 days and theresults show that the stability is poor. The solubility is low.The solubility in water is 42.22 μg/mL. The yield is lowand is in the range of 79-86%.CN105111207AForm D of freeStability is poor. XRPD is tested after being placed atform92.5% humidity for 5 days and 10 days and the resultsshow that the stability is poor. The solubility is low. Thesolubility in water is 55.26 μg/mL. The yield is low and isin the range of 66-69%.CN105111206AForm E of freeStability is poor. XRPD is tested after being placed atform92.5% humidity for 5 days and 10 days and the resultsshow that the stability is poor. The yield is low and is inthe range of 66-71%. The solvents, N,N-dimethylformamide and DMSO, used in the preparationmethod have high boiling points of 153° C. and 189° C.,respectively, which makes it difficult to remove thesolvents from the final products and easily cause solventresidue.CN105198878AForm F of freeThe solubility is low. The solubility in water is 50.98formμg/mL. The yield is low and is in the range of 53-56%.CN105198877AForm G of freeThe yield is low and is in the range of 55-76%. DMSOformused in the preparation method has high boiling point of189° C., which makes it difficult to remove the solventsfrom the final products and easily cause solvent residue.CN105198876AForm H of freeThe yield is low and is 56%. The solubility is low. Theformsolubility in water is 12.77 μg/mL.
In summary, crystalline forms of the prior art have disadvantages of complicated preparation methods, poor crystallinity, low solubility, low yield, poor stability, difficulty in drying, and ease to cause solvent residue. The inventors of present disclosure found through experiments and comprehensive analysis that Pattern 4 in CN105960407A has better properties than other crystalline forms of the prior art, such as better stability, not easy to change to other crystalline forms at room temperature, better crystallinity, easier to dry, and not easy to cause solvent residues. However, the inventors have found through experiments that Pattern 4 also has the following disadvantages such as the low solubility, high hygroscopicity, poor mechanical stability under certain mechanical force, and complicated preparation method which needs a thermal cycle between the environment temperature and 50° C. It is not conducive to the scale up of the downstream process. Therefore, it is necessary to carry out polymorph screening, so that the developed novel crystalline form can overcome the disadvantages of the prior art and is more suitable for industrial production.
The invention overcomes the disadvantages of the prior art, and the novel crystalline forms have the advantages such as simple preparation method, high solubility, good crystallinity, high purity, low hygroscopicity, good stability, especially good mechanical stability compared with the Pattern 4 of CN105960407A. These advantages make the novel crystalline form suitable for the industrial production of formulation and future drug application, which is of great economic value.